The long-range objectives of Project 2 are to develop HlV-1 vaccine regimens that stimulate broadly directed immune responses and that block HIV-1 infection in humans and control viral replication In individuals who become infected. Although the precise correlates of immunity remain undefined, significant progress has been made in this area, and it appears that both humoral and cellular immune responses may be required for an optimal HIV-1 vaccine. In this project, we will test the hypothesis that mosaic antigens will induce increased breadth of cellular and/or humoral immune responses compared with natural sequence antigens in humans. We will also test the hypothesis that boosting responses primed with our optimal vector regimen with our stable clade 0 gp140 trimer will markedly augment antibody responses. To evaluate these hypotheses, we propose the following two Specific Aims: Specific Aim 1: To determine the optimal vector regimen in humans. Study IA: A phase 1 trial to compare natural and mosaic antigens in the context of Ad26/MVA vectors. Study IB: A phase 1 trial to compare the homologous Ad26 vector regimen with a heterologous Ad26/MVA vector regimen. Specific Aim 2: To determine the impact of a protein boost with our novel Env gpl40 trimer in humans. Study 2A: A phase 1 dose escalation trial of our novel trimeric Env gp140 protein. Study 2B: A phase 1 study to compare the best vector regimen with and without a protein trimer boost.